RESUMO
Neonatal exposure to estrogenic endocrine disrupting compounds (EDCs) can advance pubertal onset and induce premature anestrous in female rats. It was recently discovered that hypothalamic kisspeptin (KISS) signaling pathways are sexually dimorphic and regulate both the timing of pubertal onset and estrous cyclicity. Thus we hypothesized that disrupted sex specific ontogeny of KISS signaling pathways might be a mechanism underlying these EDC effects. We first established the sex specific development of KISS gene expression, cell number and neural fiber density across peripuberty in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), hypothesizing that the sexually dimorphic aspects of KISS signaling would be most vulnerable to EDCs. We next exposed female rats to the phytoestrogen genistein (GEN, 1 or 10 mg/kg bw), estradiol benzoate (EB, 10 µg), or vehicle from post natal day (P) 0-3 via subcutaneous (sc) injection. Animals were sacrificed on either P21, 24, 28, or 33 (n=5-14 per group at each age). Vaginal opening was significantly advanced by EB and the higher dose of GEN compared to control animals and was accompanied by lower numbers of KISS immunoreactive fibers in the AVPV and ARC. Ovarian morphology was also assessed in all age groups for the presence of multiple oocyte follicles (MOFs). The number of MOFs decreased over time in each group, and none were observed in control animals by P24. MOFs were still present, however, in the EB and 10 mg/kg GEN groups beyond P24 indicating a disruption in the timing of ovarian development.
Assuntos
Genisteína/toxicidade , Hipotálamo/efeitos dos fármacos , Ovário/efeitos dos fármacos , Fitoestrógenos/toxicidade , Proteínas/metabolismo , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipotálamo/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Kisspeptinas , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/metabolismo , Núcleos da Linha Média do Tálamo/patologia , Ovário/crescimento & desenvolvimento , Proteínas/genética , RNA Mensageiro/análise , Ratos , Ratos Long-Evans , Ratos Wistar , Fatores Sexuais , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Konzo is a neurotoxic motor disease caused by excess consumption of insufficiently processed cassava. Cassava contains the cyanogenic glucoside linamarin, but konzo does not present the known pathological effects of cyanide. We hypothesized that the aglycone of linamarin, acetone cyanohydrin, may be the cause of konzo. This nitrile rapidly decomposes into cyanide and acetone, but the particular exposure and nutrition conditions involved in the emergence of konzo may favor its stabilization and subsequent acute neurotoxicity. A number of preliminary observations were used to design an experiment to test this hypothesis. In the experiment, young female Long-Evans rats were given 10mM acetone cyanohydrin in drinking water for 2 weeks, and then 20mM for 6 weeks. Nutrition deficits associated with konzo were modeled by providing tapioca (cassava starch) as food for the last 3 of these weeks. After this period, rats were fasted for 24h in order to increase endogenous acetone synthesis, and then exposed to 0 (control group) or 50 micromol/kg-h of acetone cyanohydrin for 24h (treated group) through subcutaneous osmotic minipump infusion (n=6/group). Motor activity and gait were evaluated before exposure (pre-test), and 1 and 6 days after exposure. Brains (n=4) were stained for neuronal degeneration by fluoro-jade B. Rats exposed to 50 micromol/kg-h of acetone cyanohydrin showed acute signs of toxicity, but no persistent motor deficits. Two animals showed fluoro-jade staining in discrete thalamic nuclei, including the paraventricular and the ventral reuniens nuclei; one also exhibited labeling of the dorsal endopiriform nucleus. Similar effects were not elicited by equimolar KCN exposure. Therefore, acetone cyanohydrin may cause selective neuronal degeneration in the rat, but the affected areas are not those expected in an animal model of konzo.
Assuntos
Encéfalo/efeitos dos fármacos , Manihot/química , Manihot/intoxicação , Degeneração Neural/induzido quimicamente , Síndromes Neurotóxicas/fisiopatologia , Nitrilas/toxicidade , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Esquema de Medicação , Discinesia Induzida por Medicamentos/diagnóstico , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Fluoresceínas , Bombas de Infusão Implantáveis , Masculino , Manihot/toxicidade , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/patologia , Núcleos da Linha Média do Tálamo/fisiopatologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Síndromes Neurotóxicas/patologia , Compostos Orgânicos , Ratos , Ratos Long-Evans , Coloração e Rotulagem , Tálamo/efeitos dos fármacos , Tálamo/patologia , Tálamo/fisiopatologiaRESUMO
We describe a 73-year-old man who developed diplopia as the initial manifestation of a left thalamic infarction. By the time he reached the emergency department, clouded consciousness precluded localization of the lesion. Results of brain MRI were initially interpreted as negative. Ophthalmologic examination several hours later disclosed a small vertical ocular misalignment attributed to skew deviation. This finding led to careful scrutiny of the upper brainstem on MRI. Comparison of the diffusion, apparent diffusion coefficient, and exponential apparent diffusion coefficient MRI studies allowed a diagnosis of subtle left thalamic infarction. The recognition of skew deviation in this setting is important because it may be the most specific indicator of a brainstem lesion.
Assuntos
Infarto Encefálico/patologia , Transtornos da Motilidade Ocular/etiologia , Transtornos da Motilidade Ocular/patologia , Doenças Talâmicas/complicações , Doenças Talâmicas/patologia , Tálamo/patologia , Idoso , Amnésia/etiologia , Afasia/etiologia , Transtornos Cognitivos/etiologia , Transtornos da Consciência/etiologia , Diplopia/etiologia , Diplopia/patologia , Diplopia/fisiopatologia , Progressão da Doença , Diagnóstico Precoce , Humanos , Imageamento por Ressonância Magnética , Masculino , Núcleos da Linha Média do Tálamo/irrigação sanguínea , Núcleos da Linha Média do Tálamo/patologia , Núcleos da Linha Média do Tálamo/fisiopatologia , Exame Neurológico , Transtornos da Motilidade Ocular/fisiopatologia , Artéria Cerebral Posterior/diagnóstico por imagem , Artéria Cerebral Posterior/patologia , Artéria Cerebral Posterior/fisiopatologia , Doenças Talâmicas/fisiopatologia , Tálamo/irrigação sanguínea , Tálamo/fisiopatologia , Tomografia Computadorizada por Raios XRESUMO
CASE REPORT: A 45-year-old patient with cervix carcinoma received combined radiochemotherapy including cisplatin. After a cumulative dose of 240 mg/m(2) the patient suddenly became somnolent and developed a severe tetraparesis and generalized seizures. After ruling out intracranial bleeding, cerebral metastases as well as infectious and metabolic causes of this condition, a severe toxic encephalopathy was diagnosed based on the clinical findings and MRI scans. After symptomatic treatment on the intensive care unit all symptoms were completely reversible. CONCLUSION: Toxic encephalopathy is a rare but dramatic complication of various cytostatic drugs. With the widespread use of cisplatin this rare disorder should be kept in mind.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/efeitos adversos , Síndromes Neurotóxicas/etiologia , Radiossensibilizantes/efeitos adversos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Antineoplásicos/administração & dosagem , Braquiterapia/efeitos adversos , Carcinoma de Células Escamosas/patologia , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/patologia , Cisplatino/administração & dosagem , Terapia Combinada , Imagem de Difusão por Ressonância Magnética , Epilepsia Generalizada/induzido quimicamente , Epilepsia Generalizada/diagnóstico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/patologia , Estadiamento de Neoplasias , Exame Neurológico/efeitos dos fármacos , Síndromes Neurotóxicas/diagnóstico , Lobo Occipital/efeitos dos fármacos , Lobo Occipital/patologia , Radiossensibilizantes/administração & dosagem , Teleterapia por Radioisótopo/efeitos adversos , Remissão Espontânea , Tálamo/efeitos dos fármacos , Tálamo/patologia , Tomografia Computadorizada por Raios X , Neoplasias do Colo do Útero/patologiaRESUMO
Periventricular hemorrhage (PVH) in the brain of premature infants is often associated with developmental delay and persistent motor deficits. Our goal is to develop a rodent model that mimics the behavioral phenotype. We hypothesized that autologous blood infusion into the periventricular germinal matrix region of neonatal rats would lead to immediate and long-term behavioral changes. Tail blood or saline was infused into the periventricular region of 1-day-old rats. Magnetic resonance (MR) imaging was used to demonstrate the hematoma. Rats with blood infusion, as well as saline and intact controls, underwent behavior tests until 10 weeks age. Blood-infused rats displayed significant delay in motor development (ambulation, righting response, and negative geotaxis) to 22 days of age. As young adults, they exhibited impaired ability to stay on a rotating rod and to reach for food pellets. MR imaging at 10 weeks demonstrated subsets of rats with normal appearing brains, focal cortical infarcts, or mild hydrocephalus. There was a good correlation between MR imaging and histological findings. Some rats exhibited periventricular heterotopia and/or subtle striatal abnormalities not apparent on MR images. We conclude that autologous blood infusion into the brain of neonatal rats successfully models some aspects of periventricular hemorrhage that occurs after premature birth in humans.
Assuntos
Animais Recém-Nascidos/fisiologia , Transfusão de Sangue Autóloga , Núcleos da Linha Média do Tálamo/fisiologia , Transtornos dos Movimentos/fisiopatologia , Envelhecimento/psicologia , Animais , Comportamento Animal/fisiologia , Encéfalo/patologia , Hemorragia Cerebral/patologia , Hematoma/patologia , Imageamento por Ressonância Magnética , Núcleos da Linha Média do Tálamo/patologia , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/patologia , Equilíbrio Postural/fisiologia , Ratos , Ratos Sprague-Dawley , Transtornos de Sensação/etiologia , Transtornos de Sensação/patologia , Transtornos de Sensação/fisiopatologiaRESUMO
The rat brain was investigated with structural and functional magnetic resonance imaging (MRI) 12 h after the arrest of pilocarpine-induced status epilepticus lasting 4 h. Histopathological data, obtained immediately after MRI analysis, were correlated with the images through careful evaluation of tissue shrinkage. Diffusion-weighted and T2-weighted imaging showed changes throughout the cerebral cortex, hippocampus, amygdala, and medial thalamus. However, only T2-weighted imaging, based on rapid acquisition relaxation-enhanced sequences, revealed in the cortex inhomogeneous hyperintensity that was highest in a band corresponding to layer V. Regional cerebral blood volume (rCBV) maps were generated using T2*-weighted gradient-echo images and an ultrasmall superparamagnetic iron oxide contrast agent. In the cortex, rCBV peaked in superficial and deep bands exhibiting a distribution complementary to the highest T2-weighted intensity. Selective rCBV increase was also documented in the hippocampus and subcortical structures. In tissue sections, alterations indicative of marked edema were found with Nissl staining in areas corresponding to the highest T2-weighted intensity. Degenerating neurons, revealed by FluoroJadeB histochemistry, were instead concentrated in tissue exhibiting hyperperfusion in rCBV maps, such as hippocampal subfields and dentate gyrus, cortical layers II/III and VI, and medial thalamus. The data indicate that:(i) T2-weighted imaging provides a sensitive tool to investigate edematous brain alterations that follow sustained seizures; (ii) rCBV maps reveal regional hyperperfusion; (iii) rCBV peaks in tissue exhibiting marked neurodegeneration, which may not be selectively revealed by structural MRI. The findings provide an interpretation of the brain response to sustained seizures revealed in vivo by different strategies of MRI analysis.